This thesis concerned about the Ru-catalyzed C-H functionalizations on the synthesis of 2-arylindole unit, silylation of heteroarenes and preparation of aryne precursor. In the first project, we developed the Ru-catalyzed C2-H arylation of N-(2-pyrimidyl) indoles and pyrroles with nucleophilic arylboronic acids under oxidative conditions. Wide variety of arylboronic acids afforded the desired product in excellent yield regardless of the substituents or functional group electronic nature. Electron-rich heteroarenes are well suited for this method than electron-poor heteroarenes. Halides such as bromide and iodide also survived, further derivatisation of the halide is shown by Heck alkenylation. In order to find catalytic on-cycle intermediate extensive mechanistic experiments have been carried out by preparing presumed ruthenacyclic complexes and C-H/D exchange reactions. It suggested that para-cymene ligand is not present in the catalytic on-cycle intermediate and we suspect that metalation occurs with electrophilic ruthenium center via SEAr mechanism. In the second project, we developed the Ru-catalyzed silylation of gramine, tryptamine and their congeners using silanes as coupling partner. The transformation worked well with many different silanes. Regarding directing group, nitrogen atom containing directing groups are more favoured than the oxygen containing directing groups. Wide range of gramines and tryptamines also yielded the desired product in poor to excellent yield. At higher temperature, albeit in low yield, undirected silylation occurred. In order to get some insights about the reaction pathway of the silylation C-H/D exchange experiments were performed, and it revealed the possibility of C4-H activation of gramines by an electron rich metal- Si-H/D experiments showed Si-H activation by Ru is easy. In the final project, we presented the closely related aryne precursors from arylboronic acids via Ru-catalyzed C-H silylation of arylboronates and their selective oxidation. Worthy of note, the aryne capture products obtained from arylboronic acids in a single purification.

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Au cours de cette thèse, nous nous sommes intéressés à l'activation de liaisons sp² et sp³ C-H catalysée par le palladium pour la préparation d'(hétéro)aryl-aryles et de biaryles. Cette méthode est considérée comme attractive pour l'environnement par rapport aux méthodes classiques, tels que Suzuki, Heck, ou Negishi. Tout d'abord, nous avons décrit que la C2-arylation directe de benzothiophènes peut être effectuée par un catalyseur du palladium en l'absence de ligand phosphine avec une grande sélectivité. Nous avons également démontré qu'il est possible d'activer les positions C2 et C5 de pyrroles pour accéder en une seule étape a des 2,5-diarylpyrroles. Des 2,5-diarylpyrroles non-symétriques ont été formés par arylation séquentielle en C2 suivie par une arylation en C5. Nous avons également étudié la réactivité de polychlorobenzenes pour l'activation de liaisons C-H catalysé au palladium. Nous avons finalement étudié l'activation sp² et sp³ sélective catalysé au palladium de liaisons C-H du guaiazulene. La sélectivité de la réaction dépend du solvant et de la base : C2-arylation (KOAc en éthylbenzène), C3-arylation (KOAc dans le DMAc) et C4-Me arylation (CsOAc/K₂CO₃ dans le DMAc). Grâce à cette méthode, une liaison sp³ C-H peu réactive a été activée. / During this thesis, we were interested in the sp² and sp³ C-H bond activation catalyzed by palladium catalysts for the preparation of (hetero)aryl-aryls and biaryls. This method is considered as cost effective and environmentally attractive compared to the classical couplings such as Suzuki, Heck, or Negishi. First we described the palladium-catalyzed direct C2-arylation of benzothiophene in the absence of phosphine ligand with high selectivity. We also demonstrated that it is possible to active both C2 and C5 C-H bonds for access to 2,5-diarylated compounds in one step, and also to non-symmetrically substituted 2,5-diarylpyrroles via sequential C2 arylation followed by C5 arylation. We also studied the reactivity of polychlorobenzenes via palladium-catalyzed C-H activation. We finally examined the palladium-catalysed selective sp² and sp³ C-H bond activation of guaiazulene. The selectivity depends on the solvent and base: sp² C2-arylation (KOAc in ethylbenzene), sp² C3-arylation (KOAc in DMAc) and sp³ C4-Me arylation (CsOAc/K₂CO₃ in DMAc). Through this method, a challenging sp³ C-H bond was activated.

Thesis advisor: Shih-Yuan Liu / Described herein are four projects focused on the elaboration of aromatic 1,2-azaborine core structures through late-stage functionalization strategies. In the first chapter, the gram scale, protecting group-free synthesis of the direct BN isostere of benzene is developed. This protocol is used to produce large quantities of pure 1,2-azaborine suitable for use in fundamental investigations. Second, the first general solution for the functionalization of the C4, C5, and C6 ring positions of 1,2-azaborines is described, featuring iridium catalyzed C-H borylation as the key strategy. Azaborine boronates produced via this method are successfully elaborated through cross coupling and oxidation to access azaborines that serve as N,N-ligands for electrophilic boron sources. The third project is an extension of the borylation/cross coupling project, and introduces the first polymer consisting of repeating azaborine units that displays highly efficient extension of conjugation along the azaborine chain. Finally, a copper catalyzed radical process is developed that enables removal of azaborine boron protecting groups during synthetic routes to simple azaborine targets of high interest. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This thesis comprises three projects on the theme of catalytic C(sp3)–H carbonylation of secondary aliphatic amines. Chapter 2 describes the development of a general methyl C–H carbonylation of secondary aliphatic amines to form synthetically useful β-lactam building blocks. Amines exhibiting a range of substitution patterns around the nitrogen functionality, and bearing a wide variety of functional groups, could be tolerated in the reaction. The desired β-lactam products were delivered in high yields, with excellent selectivity observed for the β-C–H position. Computational studies suggested that the reaction proceeds through a novel carbamoyl cyclopalladation pathway, which is distinct from classical cyclopalladation. The subsequent discovery of a selective methylene C–H carbonylation of α-tertiary amines (ATAs) is discussed in chapter 3. By employing the ATA motif, remarkable levels of selectivity for β-methlyene C–H bonds were achieved, even in the presence of traditionally more reactive methyl C–H and C(sp2)–H bonds. Once more, the reaction was found to exhibit excellent functional group tolerance, delivering highly functionalised β-lactam building blocks in high yields and selectivity. Chapter 4 presents work towards the total synthesis of the marine natural product (±)cylindricine C. The key step of this synthesis was demonstrated to proceed in good yield and excellent selectivity.

Projects were undertaken investigating the functionalisation of polyaromatic cores (chrysene, pyrene and perylene) for use in organic electronics and aqueous graphene stabilisation. In each case an iridium-catalysed aromatic C-H borylation formed a key synthetic step, allowing access to unique substitution patterns. The development of strategies for the orthogonal and asymmetric functionalisation of polyaromatic hydrocarbons was explored. In a key synthetic step 4,10-dichlorochrysene was regioselectively borylated in high yields at the 2,8-positions though C-H activation chemistry. The subsequent application of sequential palladium-catalysed Suzuki and Kumada coupling reactions to this intermediate enabled the synthesis of a series of chrysene derivatives with a unique orthogonal "A2B2" 2,8- and 4,10-substitution pattern. In addition the application of a trifluoromethylation at the borylated 2,8-positions enabled the synthesis of a donor-acceptor chrysene derivative. The effect of these substitution patterns on the photophysical and electrochemical properties of these derivatives was investigated and their potential use as organic semiconducting materials evaluated. In particular the synthesised chrysene derivatives displayed broadened UV-vis absorption spectra, redshifted fluorescence spectra, increased HOMO levels and decreased band gaps. In an extension of these aromatic substitution methodologies, pyrene and perylene aromatic cores were functionalised to perform as stabilisers for aqueous graphene dispersions, investigating asymmetric motifs that may maximise performance. A series of amphiphilic pyrene- and perylene-based alkylsulfonic acid salts were synthesised via their intermediate hydroxyalkyl derivatives. In addition the application of the previously explored aromatic C-H borylation allowed access to 7- and 5,8,11- asymmetrically substituted pyrene and perylene derivatives. Through collaboration, initial steps have been undertaken to compare and evaluate these novel stabilisers for their ability exfoliate graphite to graphene in aqueous solution.

Lolines are specialized metabolites produced by endophytic fungi, such as Neotyphodium and Epichloë species, that are in symbiotic relationships with cool-season grasses. Lolines are vital for the survival of the grasses because their insecticidal and antifeedant properties protect the plant from insect herbivory. Although lolines have various bioactivities, they do not have any concomitant antimammalian activities. Lolines have complex structures that are unique among naturally occurring pyrrolizidine alkaloids. Lolines have four contiguous stereocenters, and they contain an ether bridge connecting C(2) and C(7) of the pyrrolizidine ring. An ether bridge connecting bridgehead C atoms is unusual in natural products and leads to interesting questions about the biosynthesis of lolines in fungal endophytes. Dr. Pan, who was a graduate student in Dr. Schardl Lab at University of Kentucky, isolated a novel metabolite, 1-exo-acetamidopyrrolizidine (AcAP). She observed that AcAP was accumulating in naturally occurring and artificial lolO mutants. I synthesized an authentic sample of (±)-AcAP and compared it spectroscopically with AcAP isolated from a lolO mutant to determine the structure and stereochemistry of the natural product. I was also able to grow crystals of synthetic (±)-AcAP, X-ray analysis of which further supported our structure assignment. There were two possible explanations for the fact that a missing or nonfunctional LolO led to the accumulation of AcAP: that AcAP was the actual substrate of LolO, or that it was a shunt product derived from the real substrate of LolO, 1-exo-aminopyrrolizidine (AP), and that was produced only when LolO was not available to oxidize AP. To distinguish between the two hypotheses, I synthesized 2´,2´,2´,3-[2H4]-AcAP. Dr. Pan used this material to confirm that AcAP was an intermediate in loline alkaloid biosynthesis, not a shunt product. To determine the product of LolO acting on AcAP, Dr. Pan expressed LolO in yeast (Saccharomyces cerevisiae). When Dr. Pan fed AcAP (synthesized by me) to the modified organism, it produced NANL, suggesting that LolO catalyzed two C–H activations of AcAP and the formation of both C–O bonds of the ether bridge in NANL, a highly unusual transformation. Dr. Chang then cloned, expressed, and purified LolO and incubated it with (±)-AcAP, 2-oxoglutarate, and O2. He observed the production of NANL, further confirming the function of LolO. Dr. Chang also observed an intermediate, which we tentatively identified as 2-hydroxy-AcAP. In order to determine whether the initial hydroxylation of AcAP catalyzed by LolO occurred at C(2) or C(7), I prepared (±)-7,7-[2H2]- and (±)-2,2,8-[2H3]-AcAP. When Dr. Pan measured the rate of LolO-catalyzed hydroxylation of these substrates under conditions under which only one C–H activation would occur, she observed a very large kinetic isotope effect when C(2) was deuterated, but not when C(7) was deuterated, establishing that the initial hydroxylation of AcAP occurred at the C(2) position. In order to determine the stereochemical course of C–H bond oxidation by LolO at C(2) and C(7) of AcAP, I synthesized trans- and cis-3-[2H]-Pro and (2S,3R)-3-[2H]- and (2S,3S)-2,3-[2H2]-Asp. Feeding experiments with these substrates carried out by both Dr. Pan (Pro) and me (Asp) showed that at both the C(2) and C(7) positions of AcAP, LolO abstracted the endo H atoms during ether bridge formation. In summary, feeding experiments with deuterated (±)-AcAP derivatives and its amino acid precursors have shown that AcAP is an intermediate in loline biosynthesis. We have shown that LolO catalyzes the four-electron oxidation of AcAP at the endo C(2) position first and then the endo C(7) position to give NANL.

Ces travaux de thèse traitent de l’activation/fonctionnalisation de liaisons C-H pour la formation de dérivés d’hétéroaryles. Nous nous sommes ainsi intéressés à la réactivité de dérivés du 4-formylpyrazole pour les couplages pallado-catalysés via l’activation de liaisons C-H. La fonction formyle en C4 permet de contrôler la régiosélectivité de l’arylation. Par la suite, nous avons étudié la réactivité de 2-bromofluorènes dans ces mêmes réactions de couplage. La troisième partie se focalise sur la synthèse d’aminothiophènes et de pyrrolyl-thiophènes. L’originalité de notre approche est l’utilisation de ces composés comme précurseur dans des réactions pallado-catalysés. Enfin, la dernière partie est consacré à la réactivité du 3-bromobenzothiophène dans des réactions pallado-catalysées sans clivage de la liaison C-Br en C3 du benzothiophène. / This thesis work dealing with the activation / functionalization of CH bonds for the formation of derivatives of heteroaryl. We sum so interested in the reactivity of derivatives of 4-formylpyrazole for pallado-catalyzed via CH bond activation couplings. The formyl C4 is used to control the regioselectivity of the arylation. Subsequently, we investigated the reactivity of 2-bromofluorènes in these coupling reactions. The third part focuses on the synthesis of aminothiophenes and pyrrolyl-thiophene. The originality of our approach is the use of these compounds as a precursor in pallado-catalyzed reactions. Finally, the last part is devoted to the reactivity of 3-bromobenzothiophene in pallado-catalysed reactions without cleavage of the C-Br bond C3 benzothiophene.

Density Functional Theory (DFT) is a powerful tool for treating large organometallic structures efficiently and accurately. DFT calculations on the Hg-catalyzed oxidation of methane to methyl bisulfate in sulfuric acid suggest the lowest energy pathway involves a closed-shell electrophilic C–H activation mechanism coupled with metal alkyl reductive functionalization and oxidation by SO3. Comparison to Tl, Zn, and Cd suggests that Hg is unique in its ability to catalyze this set of reaction steps. Comparison to K2S2O8 highlights the selectivity of this C–H activation reaction as opposed to radical conditions. In contrast, DFT calculations indicate that CoIII(TFA)3 oxidizes methane through a radical TFA ligand decarboxylation pathway. A similar decarboxylation pathway is identified for MnIII(TFA)3, but the low spin ground state of TlIII(TFA)3 favors electrophilic C–H activation over this decarboxylation pathway. DFT calculations indicate that Cp(PPh2Me)Co=CF2 undergoes [2 + 2] cycloaddition with TFE by a unique open-shell singlet diradical mechanism. The significant stability of the perfluorometallacyclobutane reveals why catalytic metathesis with TFE is difficult.

Given the occurrence and diversity of nitrogen-containing molecules, the development of new amination methods is of significant importance. Indeed, a recent study shows that 60% of the FDA approved drugs contain a nitrogen heterocycle. Undoubtedly, novel methodologies arising for uncommon intermediates for the incorporation of nitrogen atoms are needed to access more complex molecules. The present document focus on the development of new methods for the formation of C-N and N-N bonds for the synthesis of acyclic and heterocyclic products. Isocyanates are useful synthons and reactive intermediates. To overcome their toxicity and instability, blocked (or masked) isocyanates have been developed: an equilibrium generates the isocyanate in-situ, allowing for safer precursors and better control over the concentration of the reactive isocyanate. This strategy enables the development of new reactivity, particularly for heteroatom-substituted isocyanates. However, reactions of oxygen-substituted isocyanates (O-isocyanates) remained severely underdeveloped. In Chapter 2, bench-stable N-oxy-carbamates and N-oxyureas are reacted under basecatalysis or thermal conditions to form the corresponding O-isocyanate intermediate in situ. In the first part of this chapter, a survey was performed and optimum experimental conditions for the controlled formation of O-isocyanate intermediates from the block precursors were found. Gratifyingly, the known side-reactions of O-isocyanates (trimerization and 1,2-shift) were avoided and different nucleophiles and substituents were studied for the controlled formation of N-oxyureas via substitution reaction of blocked O-isocyanates. Cascade reactions provided the opportunity to further develop this controlled reactivity of O-isocyanates. Herein, the first cascade-reaction of O-isocyanates is portrayed using - and -aminoester as the partners for the synthesis of hydantoin and dihydrouracil derivatives (>30 examples). Moreover, the conditions were modified to perform the reaction with -alcohol and - thioesters. Finally, evidence for the O-isocyanate intermediate is provided.